It has been reported that perhaps 50% of the occidental population and 20% of the oriental population are obese (>20% increase over ideal body mass). In fact, obesity and those having an overweight condition may have reached epidemic proportions in the United States and Western Europe. The Surgeon General of the United States estimated that in 1999 61% of adults were overweight or obese and this number might be as high as 13% for children and adolescents.
In addition to the purely aesthetic reasons for maintaining a proper weight, obesity has a pernicious effect on human health. Excessive body mass has been directly correlated to numerous disease states, inter alia, heart disease, cancer, and type II diabetes.
3-(2-Aminoethyl)-1H-indol-5-ol (serotonin) is a chemical responsible for the regulation of a wide range of CNS brain activity. As a result, extensive research has been conducted in order to understand the role of serotonin and the serotonin (5-HT receptor) in the regulation of a variety of brain-regulated physiological processes from depression to appetite control.
Pharmacologists have long known that direct activation of some 5-HT receptors reduces food consumption.1 For example, mutant mice that lack the 5-HT2C receptor are obese and activating this receptor in normal rats decreases their eating behavior. One means for treating obesity in humans was the use of fenfluramine in combination with phentermine (fen-phen). However, it was discovered in July 1997 that patients reportedly taking fen-phen developed heart valve disease and fenfluramine was subsequently voluntarily withdrawn from the market. 1. G. Curzon et al., Trends Pharmacol Sci, 13, 21-25 (1998).
Following the discovery in 1996 that melanin concentrating hormone (MCH) affects rodent feeding, researchers isolated an orphan G-protein coupled receptor that binds MCH with high affinity. It is now clear that body weight is regulated by both the central nervous system and the peripheral nervous system. Appetite and the associated cravings are CNS controlled while metabolism of food and energy expenditure are peripheral endocrine actions. It is now believed that antagonism of one melanin concentrating hormone receptor (MCH-1R) leads directly to reduction in obesity via reduction in both the desire for food (satiety) and changes in the metabolism of caloric intake (i.e. formation of fat tissue, glycogen conversion, and rate of energy expenditure).
There is therefore a long felt need for a chemical composition of matter which provides a means for controlling appetite and therefore is capable of reducing obesity in humans, said compound acting selectively as a MCH antagonist without having an affinity for the 5-HT receptors.